1. Field of the Invention
The present invention relates to a method for introducing therapeutic or medicinal agents into the uterus and fallopian tubes. More particularly, the invention relates to a method of eliciting an active or passive immunization response in the internal female reproductive organs by introducing microparticles containing a specific antibody or antigen into the vagina and allowing the microparticles to be drawn through the cervix into the uterus.
2. Description of the Prior Art
In the past, the methods of generally treating the internal reproductive organs of the female have included principally the oral ingestion or the injection of drugs into the patient in order to treat diseases and to regulate the female reproductive cycle. No methods are known of treating the uterus and fallopian tubes by introducing a drug directly into the vagina where the natural transport mechanism of the internal reproductive organs conveys the drug across the cervix into the uterus. Yet, such a direct technique of locally introducing drugs into the vagina would be highly advantageous from the viewpoint of rapidly and effectively conveying drugs across the cervix into the uterus. This technique would be especially useful for the delivery of biologically active substances, such as antibodies and antigens, directly into the uterus to increase the level of immunization of the female reproductive organs. Because systemic antibodies are not secreted by the internal reproductive organs, the immunization levels of these organs cannot be increased by systemic administration of either antibodies or antigens, but rather must be increased by local administration of antibodies or antigens to the female reproductive organs.
In the past various drugs and cosmetic agents have been encapsulated in the form of microcapsules for the purpose of delivering these agents to the vagina by slow, sustained release of the agent from the microcapsules. However, these techniques have only been useful in the treatment of the vagina and not the other internal female reproductive organs. For example, Zaffaroni in U.S. Pat. No. 3,921,636 shows a drug delivery device in which microcapsules containing a medicinal agent are incorporated in a carrier device such as a tampon, sanitary napkin or intrauterine device. Thus, a tampon containing microencapsulated contraceptive hormone can be inserted into the vagina and the hormone will be gradually released by dissolution of the microcapsules. Since the hormone is released in the vagina, the vagina is the site in which the hormone is absorbed by the body. This technique does not provide a means of delivering drugs to the uterus by transport across the cervix.
U.S. Pat. No. 3,918,452 shows a technique in which a contraceptive agent is delivered to the vagina by inserting a tampon containing microcapsules composed of a contraceptive composition into the vagina. The contraceptive agent such as a spermicide is then released slowly with time into the vagina where the contraceptive agent has its effect. In this technique the effects of the contraceptive agent are limited only to the vagina and not to any other portions of the internal female reproductive organs.
Because it would be highly desirable to be able to introduce medicinal agents or therapeutic agents directly into the uterus and Fallopian tubes by transport of said agents across the cervix, various techniques have been attempt to achieve this end. One approach that has been suggested is to encapsulate a medicinal or therapeutic agent in the form of microcapsules and then deposit the microcapsules in the vagina whereupon the microcapsules are transported. As a result of some early investigations, it is known that carbon particles from a cap containing a suspension of carbon particles, when placed over the cervix, can be recovered from the uterus after coitus, as shown by Amersbach, "Sterilitat Und Frigiditat," Muchen. Med. Wchnschr. 77: 225, 1930. This shows that nonmotile particles migrate in the female reproductive tract. It was also demonstrated by J. Trapl, "Neuve Anschauunger uber den Ei-und Samentransport in den Geschlechtsteilen de Frau," Zentralbl. Gynak. 67: 547, 1943, that even without the use of a cervical cap, carmine particles migrate thus demonstrating that nonmotile particles other than carbon also migrate.
Still other investigators, R. Krehbiel and H. P. Carstens, "Roentgen Rabbit", Am. J. Physiol. 125: 571, 1959, have shown that the passage of a radio-opaque oil, when placed in the vagina of a rabbit was blocked until after the vulva was stimulated. Stimulation of the vulva caused contraction waves which transported the oil into the uterus and up into the uterolubal junction within several seconds. Other earlier investigations found that graphite and dyes in gelatin were not transported whether applied to the vagina before or after copulation, but carmine particles in cocoa butter were transported to the uterus and tubes. The implication of the data is that the nature of the particles affects the transport process and that transport is assisted by muscular contractions. Hartman, in "How Do Sperms Get Into the Uterus?" Fertil. and Steril 8: 403, 1957, concluded that in the transport of sperm in the reproductive tract, transport occurs principally by cooperation of the particles with the musculature of the female reproductive tract. He also concluded that the function of the flagellum of the sperm is to aid in the penetration of the head of the sperm into the corona radiata, the zona pellucida and the vitelline membrane of the ovum. G. M. Duncan and D. R. Kalkwarf, "Sustained Release Systems for Fertility Control," in Human Reproduction: Conception and Contraception, edited by E. S. E. Hafez and T. N. Evans, Harper and Row, New York, 1973, have concluded from experiments that non-motile particles which are about the size of the head of the sperm migrate directionally through the cervix to the fallopian tubes. Thus, the reference indicates that non-motile particles of a size of 5 .mu.m or less migrate throughout the internal reproductive organs when introduced into the vagina. However, when microcapsules of progesterone encapsulated within a suitable wall material such as cellulose acetate butyrate and of a size ranging from 5 to 1400 .mu.m were introduced into the vagina, the microcapsules did not migrate across the cervix into the uterus, but rather were transported in the reverse direction. Therefore, the reference clearly suggests that microcapsules of a size greater than 5 .mu.m will not migrate inward to the internal female reproductive organs.
A need therefore, continues to exist for a method by which various disorders and diseases of the internal female reproductive organs can be locally treated by applying microparticles of various medicinal and therapeutic agents to the vagina and allowing the natural transport mechanism of the organs to draw the microparticles across the cervix into the uterus where the medicinal or therapeutic agent is delivered to the uterus and other internal organs.